PROJECT SUMMARY/ABSTRACT Increased comorbidities such as nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), are an emerging problem in HIV-1 infection but the mechanisms are unclear. Understanding the mechanisms by which inflammation and chronic immune dysfunction in chronic HIV infection drive NAFLD and NASH despite potent antiretroviral therapy (ART), will provide new therapies to reduce HIV-1 related morbidity. Statins are inadequate treatment for HIV-1-related inflammation, immune activation and comorbidities and novel therapies are needed. Novel therapies such as apoA-I mimetic peptides that target oxidative stress and oxidized lipids and can also target proinflammatory phenotypes of macrophages can complement statins and can be promising therapies for HIV-1 related comorbidities. Before these novel therapies are tried in the clinic, the exact mechanisms of action need to be defined. While several human studies have studied HIV-1 related comorbidities related to aging such as NAFLD and NASH, they are all limited by several confounders. Given the complex pathogenesis of NAFLD and NASH, it is impossible to directly study in humans mechanisms that drive NAFLD and NASH. A robust animal model is needed to understand NAFLD/NASH. The humanized mouse model represents to date the most advanced in vivo model to study HIV pathogenesis. The immunodeficient mice that undergo bone marrow/liver/thymus (BLT) transplantation have better engraftment of human hematopoietic stem cells than any other mouse strain. We hypothesize that the BLT mice can be used as a model to directly study therapies for NAFLD/NASH. It is becoming clear that macrophage/monocyte (M/M) dysfunction may accurately predict morbidity and mortality in ART-treated individuals. Thus, the current proposal will explore whether the BLT mouse can be used as a model to study whether apoA-I mimetics can complement statins to attenuate proinflammatory/activated M/M (peripheral blood) and liver inflammation, steatosis and fibrosis related to HIV-1, oxidized lipids and human M/M. Given that HIV-1-infected persons on ART may continue to have NAFLD and NASH such an approach could reduce the excess morbidity and mortality remaining despite ART. This work is innovative, has a potential impact on public health and directly addresses NIH's overarching HIV/AIDS research priorities regarding HIV-associated comorbidities (NOT-OD- 15-137). This grant application also directly addresses the scope of this R21 grant that encourages innovative research (novel therapies for NAFLD and NASH within a physiologically relevant mouse model).